The present invention relates to an implant and to a method for producing an implant and, more particularly, to implants having cavities for absorbing therapeutic agents.
Here, the term xe2x80x9cimplantxe2x80x9d is first of all, to be understood in a narrow sense, as referring to an element, at least temporarily insertable into the body of an animal or human, which may perform, e.g., therapeutic, support and/or joint functions, like temporary implants, for example the so-called xe2x80x9cseedsxe2x80x9d, or stents for tumor treatment or therapy, tracheal stents and the like. However, in a broader sense, this term is also be understood as referring to elements or the like being able to be brought, preferably temporarily, into contact with the body on the outside.
Implants in the form of stents are applied, e.g., for supporting widened vessels. After having widened constricted vessels, these tube-shaped inserts are inserted and then radially widened so that the stents support the vessel walls from the inside.
The stents grow into the vessel walls within about one to three months. A local radioactive irradiation of the vessel walls has proved to be effective in preventing an overgrowth of the vessel walls towards the inside which may lead to a re-stenosis, i.e. a re-constriction. The following possibilities present themselves in this respect.
Firstly, a balloon catheter filled with a radioactive liquid is applied. Since the balloon catheter at least partly closes the vessel in its expanded condition, contact with the vessel wall and thus application of the balloon catheter is very strongly limited in time. In order to locally obtain an effective dose, very large activity amounts must thus be applied which leads to technical problems in protection against radiation. In addition, there is a very high risk for the patient in the event of a mechanical failure of the balloon.
Secondly, a sealed radiation source may be inserted via a catheter. Here, because of the limited dwell time of the catheter in the vessel, great amounts of activity must also be applied which demands a great technological effort with regard to protection against radiation. Furthermore, there is the problem of centering the radiation sources.
Thirdly, radioactive stents may be applied. As a result, the aforementioned problems and risks are avoided and the desired or effective dose may be achieved with low amounts of radioactivity over an extended exposure time.
In the last case, i.e. the radioactive embodiment of the stents, it is already known to provide ion implantation. Here, radioactive phosphorus (32P) is implanted in existing stent surfaces by means of an ion beam. Further, it is known that a nickel-titanium stent may be bombarded with protons in a cyclotron or the like, in order to activate the titanium contained in ordinary nickel/titanium alloys into radioactive vanadium (48V).
Both ion implantation and proton activation are marked by a great technological effort, i.e. the stents can only be produced on a xe2x80x9ccustom-made basisxe2x80x9d. Moreover, both methods are hitherto limited to a few manufacturing sites and a few radionuclides.
A further method for producing radioactive stents is provided by electrochemically precipitating radioactive rhenium on stent surfaces and then by covering them with a gold a layer as a protective layer. Here, as in all multi-layer structures, there is the risk of segmentation, i.e. detachment, which is very high for stents because of the deformation during the radial widening on the inside of the vessels. Even if only the protection layer is dissolved or in the event that it was applied incompletely, there is the risk that radioactive rhenium lying freely on a large surface area may then be partly dissolved in the blood and may be transported to other locations in the body with undesirable consequences.
Moreover, having drugs act as locally as possible may be meaningful in order to prevent, e.g., an expulsion of the implant or to perform local tumor treatment, for example.
A stent is already known from CA-A-2,235,031 corresponding to EP-A-0 875 218 which forms the starting point of the present invention; a stent which comprises a non-porous support with a porous covering layer in one embodiment. The porous covering layer is formed of sintered metal particles. A drug or a therapeutic agent is absorbed in the pores of the porous covering layer and it may be re-released from the stent in the implanted state if the porous covering layer is covered with a dissolvable or permeable covering layer for example. A radioactive material may also possibly be applied as a drug.
In the known stent, it is detrimental that the sintered metal particles of the porous covering layer form very irregular, indefinite pores. Accordingly, in the case of a drug to be released, only a relatively indefinite release behavior is achieved.
When a radioactive material is absorbed in the pores of the covering layer, there is the risk that the radioactive material uncontrollably and undesirably escapes because of irregular pores with indefinite openings. The optionally provided coating of the covering layer does not provide sufficient protection in this respect.
The mechanical strength and rigidity of the covering layer formed from the combined sintered metal particles is not very good, especially when deforming the stent. In particular, there is the risk that at least some individual metal particles break away from the covering layer. In addition, there is the risk of segmentation of the covering layer, especially in the radial widening of the stent. Here, there is the risk that, for example, blood circulation will transport portions of the covering layer to other locations in the body with undesirable consequences. This risk is particularly high in the application of radioactive material which, as a drug or a therapeutic agent, should remain fixed in the porous covering layer.
In addition, nickel, in particular, is suspected in metal implants of at least favouring excess cell growth, in particular in the area around an inserted implant. Moreover, other metals from metal surfacesxe2x80x94even when only in small amountsxe2x80x94which may also be dissolved by body fluids, such as blood, are increasingly made responsible for undesirable consequences or at least unpredictable reactions in the body. In this respect, the large surface area of the metal particles from the known stent""s porous covering layer which may come into contact with body fluids or with the body tissue growing into the porous covering layer, is particularly detrimental. However, e.g., the application of ceramic covering layers or the coating of metal surfaces for use with implants is already known, for example from DE-A-43 11 772, DE-A 40 40 850, DE-A-32 41 589 or EP-A-0 520 721.
The object of the present invention is to provide an implant and a method for producing an implant so that an implant, in particular formed as a stent, may be produced relatively simply, wherein in particular the aforementioned drawbacks of the prior art may be avoided or at least minimized and wherein a therapeutic agent may be absorbed by the implant andxe2x80x94if desiredxe2x80x94is locally re-releasable in the implanted condition, and in particular so that the implant, in particular a stent, enables radionuclides to be fixed securely on or in the surface.
In particular, the covering layer comprises a plurality of defined cavities with separate openings to the surface of the covering layer for absorbing at least one therapeutic agent. The term xe2x80x9ccavitiesxe2x80x9d should also be understood here as defined vacancies in crystal structures or the like which are suitable for absorbing a therapeutic agent.
Unlike the prior art, the structure of defined and preferably separate cavities in the covering layer allows very precise amounts of a therapeutic agent to be stored in the cavities, to be fixed in the cavities if necessary and to be re-releasedxe2x80x94if desiredxe2x80x94in the implanted condition under definite conditions, such as with a desired release rate.
The term xe2x80x9ctherapeutic agentxe2x80x9d should be understood in accordance with the present invention as drugs in the broadest sense, optionally also radioactive material or other therapeutic substances. In particular, all therapeutic agents, which in EP-A-0 875 218 are designated as xe2x80x9cmedicationxe2x80x9d or receptor-agonists, receptor-antagonist, enzyme inhibitors, neurotransmitters, cytostatitics, antibiotics, hormones, vitamins, metabolic substrates, anti-metabolites, diuretics, and the like are also considered to be therapeutic agents in accordance with the present invention.
In addition, an implant as proposed is provided with a support and a covering layer, wherein preferably the covering layer at least essentially consists of a metal oxide and/or ceramic material. In particular, the covering layer essentially comprises aluminum oxide, magnesium oxide tantalum oxide, iron oxide and/or titanium oxide. Such a covering layer is relatively easy to produce, for example via electrolytic precipitation and oxidization, and it forms a highly chemically and mechanically stable, in particular, very dense coating of the support. This coating may prevent, at least to a large extent, (ionic) dissolution of nickel or other metals from the support. Excess cell growth induced by the dissolved metals may thus at least be minimized in the surroundings and in the contact area of the implant respectively.
A simple structure of the cavities in the covering layer is preferably achieved by anodic oxidization of a surface layer which may be part of the support or of a coating deposited thereon.
Similarly-shaped cavities of defined dimensions may thus be formed in a simple way. Preferably, highly similarly-shaped cavities may be produced very simply by electrolytically forming an aluminium oxide layer as a covering layer on the surface of the support. In such an artificial oxidization of aluminium (anodization), defined cavities may be formed in dependence with the applied voltage. Apart from aluminium oxide, all the so-called valve metal oxides, e.g. titanium and tungsten oxides, are particularly suited for this purpose. Furthermore, magnesium oxide is also useful.
By varying the electrical voltage during the anodization, the diameter of the cavities and the surface density of the cavities, i.e., the number of cavities per unit surface, may be varied. The length of the cavities depends on the duration of the anodization. As a result, the shape of the cavities may be controlled in large ranges, so that e.g. in view of a desired release behavior (release rate, release amount), an optimized shape of the cavities may be produced in a simple way. For example, the cavities are formed at least essentially as tubes and extend from the surface of the covering layer, essentially perpendicularly into the inside of the covering layer, wherein the portion of the cavities and/or their openings are reduced in diameter or proportionally in area in order to obtain desired properties.
When needed and depending on the application, several therapeutic agents which, for example, are re-released in succession and/or with an irregular release rate in the implanted state, may be absorbed by the cavities. For example, therapeutic agents of different molecular size may thus be absorbed in different cavities of suitable dimensions of the covering layer of the implant. If necessary, the cavities or their openings to the surface of the covering layer, may also be formed small as compared with the components normally contained in body fluids, like blood, in particular proteins, with the result that an otherwise occurring dissolution or wash-out of the therapeutic agent situated in the cavities does not occur through blood macro-molecular components or the like, as the latter cannot penetrate into the cavities.
The integration of the cavities in the covering layer of the support makes a relatively thin structure possible with a correspondingly low tendency to segmentation, i.e. a structure with favorable mechanical properties.
The forming of cavities in certain locations with a relatively low superficial extent with respect to the superficial extent of the covering layer leads to the advantage that the mechanical properties of the covering layer essentially only depend on the material of the covering layer and not on the therapeutic agent or the like in the cavities. Accordingly, an optimized covering layer with regards to the large mechanical stress in stents can be applied on the one hand and on the other hand optimally suitable therapeutic agents with regards to the treatment can be used.
Basically, the cavities may be linked with one another. But, preferably, the cavities are formed separated from one another, preferably with respect to low height or thickness of the covering layer.
In particular, in the case of separately formed cavities, it is possible to arrange a therapeutic agent or several therapeutic agents in the cavities in a different concentration or amount or with different release behavior in order to achieve, for example, a desired inhomogeneous dose distribution in time and/or in space, with, e.g., a higher dose at the ends of a stent.
The introduction of the therapeutic agent and/or the complexing agents or binding partners in the cavities of the covering layer and by subsequent addition of the therapeutic agent or the complexing agents or binding partners, so that it (they) is (are) absorbed by the cavities or sucked into them. If necessary, this is repeated, e.g., for cavities in certain surface areas, in particular end areas of the implant, in order to achieve a local increase in the amount of absorbed therapeutic agent.
Alternatively or additionally, introduction of the therapeutic agent or of the binding partners in the cavities may be achieved or assisted by means of ultrasound which may purge air or other gases present in the cavities upon dipping the implant into the agent to be introduced.
A further aspect of the present invention consists in fixing or binding the therapeutic agent or the therapeutic agents in the cavities according to needs, for example ionically via hydrogen bridges, via complexing agents, via Van der Waal forces, or the like in order to achieve the desired release or liberation of the therapeutic agent or of the therapeutic agents. Bonds are also possible which are chemically or enzymatically cleaved or broken up in biological systems and thereby cause a release. Desired properties of the cavities may be obtained relatively easily by chemically altering the walls of the cavities, in particular by chemically fixing suitable binding partners for the relevant therapeutic agent on the wall surfaces.
Finally, it should be pointed out that the implant as proposed may also be provided with cavities open to the outside in the covering layer, wherein the size of the cavities may be selected so that cells or portions of cells from the body tissue adjacent to the implant may grow into the cavities and thus, for example, a very secure anchoring of the implant in the body may be achieved.
In addition, there is the possibility of covering the covering layer or the openings of the cavities with a cover layer as protective layer. This cover layer may be made very thin, as essentially it is only used for obtaining the desired surface properties or a covering up of the material of the covering layer. For example, depending on the application, the cover layer may be formed so that it dissolves or loosens from the surface of the covering layer in the body, for example due to the body""s temperature, to artificial heating, chemical or enzymatic effects from liquids or body-specific substances, or so that it is permeable for a therapeutic agent to be absorbed in the cavities. In particular, the cover layer may be formed like the one in the coating of porous material disclosed in EP-A-0 875 218.
In the specially provided application of radioactive material as therapeutic agent, an essential aspect of the present invention is that the radioactive material is not localized or arranged over the entire surface, but only in individual locations and in the covering layer of a support, respectively. The covering layer may basically be formed by a surface layer, i.e. an upper portion, of the support or in particular by a layer or coating applied on the surface of the support. Thus, it is possible to form the cavities or their openings to the surface of the covering layer, small as compared with the components normally found in blood, particularly proteins, so that in the case of exposure to radioactive material over a large area, no normally occurring dissolution or removal of the radioactive material by macromolecular blood components occurs, as the latter cannot penetrate into the cavities.
A further advantage provided by the cavities lies in that the walls of the cavities create a very large inside surface area. This internal surface represents an essentially larger surface than the outside surface of the covering layer and accordingly it allows a particularly tighter or stronger binding of more radioactive material as compared with standard multi-layer structures.
Another advantage provided by the arrangement of the radioactive material in the cavities lies in the different concentration of radioactive material according to need in order to achieve a desired spatial inhomogeneous dose distribution with, for example, a higher dose at the ends of a stent, by xe2x80x9cfillingxe2x80x9d the cavities with different amounts of radioactive material in some areas of the surface.
Preferably, the cavities are formed at least essentially as tubes and extend from the surface of the covering layer, essentially perpendicularly into the inside of the covering layer, wherein the cross-sections of the cavities and/or their openings are preferably dimensioned so small that at least most of the proteins normally present in blood cannot penetrate into the cavities because of their molecular size, especially when they are only partly filled. Accordingly, the radioactive material provided in the cavities cannot be carried away by blood.
The use of an oxide layer, in particular of aluminium oxide, as a covering layer results in the additional advantage that the oxide layer in a liquid is subject to a sort of swelling which results in closure or further reduction of the opening area of the openings of the cavities in the covering layer, thereby providing an obstacle or impediment to the penetration of the relatively large proteins in blood. Of course, this swelling should be taken into account, when for example in a desired release of some therapeutic agents, the openings should not be closed.
Preferably, the introduction of the radioactive material and/or of the complexing agents in the cavities may be achieved by evacuating the cavities and then adding the radioactive material or the complexing agents which are then absorbed by the cavities or sucked into them, so to speak. When needed, this may be repeated e.g. for cavities in certain areas of the surface, in particular the end areas of the implant in order to achieve a local increase in radioactivity.
A further, independent aspect of the present invention lies in that the radioactive material, i.e., a particularly predetermined amount of a radionuclide or of different radionuclides, is to be fixed preferably in the cavities via complexing agents, such as amines, phosphines, carboxylates, and/or thiols. In particular, thiols are provided as complexing agents and for example, technetium and rhenium as radioactive material, since technetium(V) and rhenium(V)-compounds form metal complexes with sulphur-containing ligands which exhibit an extremely high stability in vivo. On the other hand, as another example, it is better to bind radioactive copper via carboxylates. With the help of complexing agents, in particular radioactive cations (metals) may thus be very tightly bound chemically, in particular in the cavities or pores of the covering layer. Preferably the complexing agents themselves are fixed or formed on the walls of the cavities, in particular by silanization, so that the complex is entirely fixed on the surface or in the covering layer of the support.
Alternatively, a binding of radioactive (non-metal) anions, for example iodine, may also be provided by forming a complex with appropriate complexing agents or with appropriate binding partners, for example in metals fixed in the cavities, such as noble metals, in particular silver.
A further, independent, essential aspect of the present invention lies in that different radionuclides with correspondingly different half-life times and emission energies, such as 186Re (Txc2xd=90 hrs, Excex2max=1.071 MeV) and 188Re (Txc2xd=16.7 hrs, Excex2max=2,116 MeV), are used together in predetermined amounts and ratios as a blend or mixture, respectively. An optimal dose distribution may thus be obtained for the relevant application both with respect to space and time considerations. The fixing of different radionuclides is especially enabled by the provision of cavities for absorbing the radionuclides, since the mechanical properties of the radionuclides or of the compounds formed with the radionuclides in the cavities play a minor role for the mechanical properties of the covering layer anyway because of the relatively small expansion of the cavities, so that radionuclides or radionuclide compounds which may not normally be used for large surface coatings may be absorbed in the cavities and fixed therein.
Moreover, there is the possibility of covering the covering layer or the openings of the cavities with a cover layer, for example in gold, as a protective layer. This cover layer may be made very thin as essentially it is only used for achieving the desired surface properties or a covering of the material of the covering layer, wherein, unlike the prior art, preventing contact between radioactive material and blood is of secondary importance, as the radioactive material is fixed in the cavities chemically and so it is already protected by the cavities anyhow. Furthermore, an essentially better adhesion of the cover layer on the covering layer may be achieved because of the free choice of materials, as essentially the mechanical and chemical properties of the covering layer are not influenced by the radioactive material used.